去泛素化酶USP19的功能调节机制及结构基础

Ubiquitin-Specific Protease 19 (USP19) is a multi-domain deubiquitinating enzyme, which is probably involved in diverse important cellular functions. USP19 contains an insertion domain, including UbL (Ubiquitin-like) and MYND（myeloid-Nervy-DEAF-1）domains, in its catalytic USP domain. It is putatively proposed that this insertion domain plays a role in regulating the catalytic activity and biological function. In addition, there exist two CS (CHORD-containing proteins and Sgt1) domains in its N-terminus that can interact with HSP90. In this project, by using biochemistry and cell biology approaches, we will investigate the regulatory effect of UbL and MYND domains on the activity and function of USP19, the interaction and structural basis of the two CS domains with HSP90, and the effects of USP19 on the protein level and aggregation of ataxin-3 in cell model. This study will reveal the domain-mediated interactions and the functional regulation of USP19, and also provide the molecular mechanism underlying USP19 functions in cellular protein quality control.

泛素特异蛋白酶USP19是一种具有多结构域的去泛素化酶，它可能参与调控多种重要的细胞功能。USP19的催化结构域中含有一段插入序列，包含UbL (Ubiquitin-like)和 MYND (myeloid-Nervy-DEAF-1)结构域，我们推测它们可能参与了USP19催化活性和生物功能的调节。另外，USP19的N-端含有两个CS (CHORD-containing proteins and Sgt1）结构域，可能与HSP90相互作用。本项目将采用生物化学和细胞生物学的技术方法研究UbL和MYND插入肽段对USP19活性和功能的调节作用，CS结构域与HSP90相互作用的生物功能及结构基础，以及USP19对细胞模型中Ataxin-3蛋白的量和积聚的影响。通过研究将揭示USP19的相互作用和功能调节以及其所参与的细胞内蛋白质质量控制的分子机制。

USP19是一种具有多结构域的泛素特异蛋白酶，它可能参与调控多种重要的细胞功能。本项目应用生物化学和细胞生物学的技术方法研究了USP19的活性和功能调节作用，CS结构域与HSP90相互作用的生物功能及结构基础，以及USP19对细胞模型中底物蛋白的量和积聚的影响及分子机制。研究发现USP19通过分子伴侣HSP90调节PolyQ底物蛋白Ataxin-3和Huntingtin蛋白的量和积聚过程。通过研究，我们加深认识了USP19 通过HSP90参与细胞内易积聚蛋白质的质量控制，即底物蛋白的命运决定：再折叠、积聚和降解的机制。